Project Summary In current risk assessment and counseling practices, all women who test positive for a deleterious BRCA1/2 mutation are quoted the same general range of ovarian cancer risk and are given the same recommendation regarding utilization of risk reducing salpingo- oophorectomy (RRSO) and other preventive measures. We have recently published a model that reports substantial and clinically relevant differences in risk depending on the specific mutation a woman has inherited. In particular, we have recently shown that specific mutations confer an increased risk or earlier age of onset for breast or ovarian cancer compared with the generic risk estimates made for any BRCA1/2 mutation. In addition, risk estimates that consider previous exposure to important risk factors (e.g., reproductive history, oral contraceptive use, or preventive surgery use) may have a large impact on cancer risk estimates in this population. More precise risk information could be critical for optimal decision-making for women who are considering cancer prevention strategies. Based on these initial observations, we propose to develop precision absolute risk models that incorporate information about mutation risk group, to apply in vitro methods to identify new clinically relevant BRCA1/2 mutations and validate their capacity to cause disease, and to gain a better understanding of how personal values affect how individual women interpret and act on risk estimates, for use in a future decision aid intervention. Thus, this proposal will develop a ?precision prevention? approach to BRCA1/2-associated cancer risk to lower the chances a woman will die from ovarian cancer, and will have immediate translational impact for women with BRCA1/2 mutations.